Consultation in the design and implementation
Benefits & Business Case
Identification of the benefits for considering continuous processing in process research and in manufacturing.
Through first hand experience, I know that the enhanced control and reduced the level of manufacturing variance afforded through operating continuously, improves the quality of medicines for the benefit of patients and manufacturers; ultimately this will reduce the incidence of quality investigations in pharma.
To realise the benefits of this technology, it is essential to have an aligned vision between R&D and manufacturing in your organisation or with your contract manufacturer. Moving ahead with a new technology requires organisational courage; the source of this courage is a clear vision, communicated properly such that everyone can buy in. I can help drive this discussion in your organisation, to clarify what the criteria are and what it really means for project leaders, project scientists and manufacturing colleagues.
Process design
Definition of work flow to change a single or multiple stage of a batch process into a continuous process
By focusing on the value added steps in a synthetic sequence, I can quickly identify which unit operations could be removed and produce a process intensification work flow; experimental work that is aimed to challenge the traditional thinking around the current process.
Portfolio review
Expert review of your portfolio of products to identify opportunities for continuous processing
This process is fundamentally linked to having a robust vision for why, how and when, within your organisation; what is the appetite to embrace change? And at what stage in the development cycle? Once this is established I can work with your scientists to systematically review the processes and manufacturing strategy for each asset, to make an assessment of where the opportunities are based on both the science and the manufacturing strategy.
Equipment selection
Definition of work packages to enable equipment selection for continuous processing
The development of a continuous process invariably starts in a batch flask. In batch, is it impossible to replicate the environment in a plug flow reactor. A number of unexpected problems can surface when switching from the flask into flow equipment and the earlier you can find these the better. There are things that can only happen at the point of injection that are not so easy to predict or explain by computational fluid dynamics (CFD). Instead these issues are often only identified through experimentation. It is important to try to get as much experience of different equipment types, as quickly as it is safe to do so. Remembering, to challenge the notion that a certain type of process requires a specific type of reactor; without challenge, this can lead to an over complicated and costly solution being implemented. What is the simplest equipment choice you can make? I can help to challenge the thinking on your project and share some of the phenomena we have witnessed; some are very subtle and not at all obvious and could lead to costly delays further down the line.
Integration & Implementation
How to best integrate continuous stages with batch stages
There may be good reasons to design a hybrid approach for your process because it affords the greatest flexibility offering the best attributes of both technologies. I can help identify which steps in a process should remain as batch processes and what other steps should be converted to run continuously. Consideration has to be made to the stability of batch products which are now feeding the continuous unit operation(s) and vice versa. Designing a hybrid process that can operate and integrate easily with batch steps, is as much part of the process design thinking as choosing a new reagent or solvent.
Operational philosophy
How best to operate, start up and shut down, diversion strategy, maintenance of state of control
The management of material made on the approach to a state of control or during a process disturbance, requires careful consideration. I can help define a strategy for your process. Knowledge of the equipment performance, in conjunction with the process parameters being in a state of control, can become the backbone of the decision to collect or reject material. These considerations are equally important for single or multiple unit operations. Although, in a multiple stage process it is likely that all transitional materials would be diverted to waste to prevent decision making criteria becoming exponentially complicated. This thinking needs to be built into the design of the process as early as possible, such that the decision making criteria are clear and can be tested as part of process verification. Whereby the goal would be to reach the utopia of operator agnostic decision making; faced with the same processing situation the night shift team takes precisely the same course of action as the day shift team.
To further minimise complexity, the process should be designed to avoid requiring an off-line sample being taken or deferring to a process specialist to confirm that the process is under a state of control, because these options may not be available on the factory floor at 2am in the morning. I can challenge your team to build this into their thinking during process design.
Robustness
Work plan to assess equipment and process robustness
Operating continuously requires a very different mindset to batch processing. Managing process disturbances needs to be a pre-planned change to enable just in time problem solving and avoid plant shutdowns. Every opportunity to perform representative equipment tests in a lab/plant environment should be sort; I can help you design these experiments. Very often, the first development campaigns in the equipment, evolve into an equipment performance saga and not the intended process capability test.
PAT
The application and integration of Process Analytical Technologies
The use of PAT in development can be a really important tool to provide additional process understanding and process performance data. As the process transitions between R&D and manufacturing, there may be good reasons to include the same suite of PAT tools, perhaps to enable smooth technical transfer and on-line data to provide the side by side comparison of process performance between R&D and the factory. However, ahead of registration and inspection, R&D and manufacturing need to have a joined up PAT strategy because there is no such thing as PAT for information only in the factory; the inspector may ask each of the operators to explain what actions would follow the discovery of atypical PAT data, what prompts the discovery and where is the actionable procedure written down?
Based upon the process requirements and the control strategy, I can help your team to devise a PAT strategy suitable for R&D and manufacturing.
Regulatory considerations
Batch definition, material traceability, control strategy, divert to waste, parametric control and continuous crystallisation.
The message from regulatory agencies has been very supportive to encourage the adoption of continuous manufacturing for both drug substance and drug product. To date, the small number of regulatory approvals have been predominately multiple drug product unit operations rather than multiple wet chemistry stages. My first hand experience of engagement with regulatory agencies ahead of filing a multistage API process, was very positive but also a pretty mixed bag. It became apparent that the grasp of the technology varied widely from agency to agency. This only further strengthens the argument for engagement ahead of filing. I can share my experiences with your team and help them prepare for regulatory meetings, to ensure that you all get the most value of these important opportunities.
